Pipe Steven W, Leebeek Frank W G, Recht Michael, Key Nigel S, Castaman Giancarlo, Miesbach Wolfgang, Lattimore Susan, Peerlinck Kathelijne, Van der Valk Paul, Coppens Michiel, Kampmann Peter, Meijer Karina, O'Connell Niamh, Pasi K John, Hart Daniel P, Kazmi Rashid, Astermark Jan, Hermans Cedric R J R, Klamroth Robert, Lemons Richard, Visweshwar Nathan, von Drygalski Annette, Young Guy, Crary Shelley E, Escobar Miguel, Gomez Esteban, Kruse-Jarres Rebecca, Quon Doris V, Symington Emily, Wang Michael, Wheeler Allison P, Gut Robert, Liu Ying P, Dolmetsch Ricardo E, Cooper David L, Li Yanyan, Goldstein Brahm, Monahan Paul E
From the Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor (S.W.P.); the Department of Hematology, Erasmus University Medical Center, University Medical Center Rotterdam, Rotterdam (F.W.G.L.), Van Creveldkliniek, University Medical Center Utrecht, University Utrecht, Utrecht (P.V.V.), Vascular Medicine, Amsterdam University Medical Center, University of Amsterdam (M.C.), Amsterdam Cardiovascular Sciences, Pulmonary Hypertension and Thrombosis (M.C.), and uniQure Biopharma (Y.P.L.), Amsterdam, and University Medical Center Groningen, Groningen (K.M.) - all in the Netherlands; Yale University School of Medicine, New Haven, CT (M.R., S.L.); American Thrombosis and Hemostasis Network, Rochester, NY (M.R.); the Department of Medicine and UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill (N.S.K.); the Center for Bleeding Disorders and Coagulation, Department of Oncology, Careggi University Hospital, Florence, Italy (G.C.); the Department of Hemostaseology and Hemophilia Center, Medical Clinic 2, Institute of Transfusion Medicine and Immunohematology, University Hospital Frankfurt, Frankfurt (W.M.), the Comprehensive Care Hemophilia Treatment Center, Vivantes Klinikum im Friedrichshain, Berlin, and the Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, University of Bonn, Bonn (R. Klamroth) - all in Germany; the Department of Vascular Medicine and Hemostasis, Hemophilia Center, University Hospitals Leuven, Leuven (K.P.), the Division of Hematology, Cliniques Universitaires Saint-Luc, Brussels (C.R.J.R.H.), and Université Catholique de Louvain, Louvain-la-Neuve (C.R.J.R.H.) - all in Belgium; the Department of Hematology, Rigshopitalet Copenhagen, Copenhagen (P.K.); National Coagulation Centre, St. James's Hospital, Dublin (N.O.); Barts and the London School of Medicine and Dentistry, Queen Mary University of London (K.J.P., D.P.H.), and the Royal London Hospital Haemophilia Centre, Barts Health NHS Trust (D.P.H.), London, University Hospital Southampton and National Institute for Health and Care Research Clinical Research Facility, Southampton (R. Kazmi), and Cambridge University NHS Foundation Trust, Addenbrooks Hospital, Cambridge (E.S.) - all in the United Kingdom; the Department of Translational Medicine, Lund University, and the Department of Hematology Oncology and Radiation Physics, Skåne University Hospital - both in Malmö, Sweden (J.A.); the Department of Pediatrics, University of Utah, and Primary Children's Hospital, Salt Lake City (R.L.); University of South Florida, Tampa (N.V.); the Department of Medicine, Hemophilia and Thrombosis Treatment Center, San Diego (A.D.), the Cancer and Blood Disorders Institute, Children's Hospital Los Angeles (G.Y.), the Orthopaedic Hemophilia Treatment Center, the Luskin Orthopaedic Institute for Children (D.V.Q.), and the University of Southern California Keck School of Medicine (G.Y.), Los Angeles, and the Center for Inherited Blood Disorders, Orange (E.G.) - all in California; Arkansas Children's Hospital, Pulaski, and University of Arkansas for Medical Sciences, Little Rock (S.E.C.); University of Texas Health Science Center, McGovern Medical School, and Gulf States Hemophilia and Thrombophilia Center - both in Houston (M.E.); Washington Center for Bleeding Disorders and University of Washington, Seattle (R.K.-J.); Hemophilia and Thrombosis Center, University of Colorado Anschutz Medical Campus, Aurora (M.W.); the Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville (A.P.W.); uniQure, Lexington, MA (R.G., R.E.D., D.L.C.); and CSL Behring, King of Prussia, PA (Y.L., B.G., P.E.M.).
N Engl J Med. 2023 Feb 23;388(8):706-718. doi: 10.1056/NEJMoa2211644.
Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement.
In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×10 genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed.
The annualized bleeding rate decreased from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P<0.001), demonstrating noninferiority and superiority of etranacogene dezaparvovec as compared with factor IX prophylaxis. Factor IX activity had increased from baseline by a least-squares mean of 36.2 percentage points (95% CI, 31.4 to 41.0) at 6 months and 34.3 percentage points (95% CI, 29.5 to 39.1) at 18 months after treatment, and usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant in the post-treatment period (P<0.001 for all three comparisons). Benefits and safety were observed in participants with predose AAV5 neutralizing antibody titers of less than 700. No treatment-related serious adverse events occurred.
Etranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to the annualized bleeding rate, and it had a favorable safety profile. (Funded by uniQure and CSL Behring; HOPE-B ClinicalTrials.gov number, NCT03569891.).
中重度B型血友病患者需终身持续补充凝血因子IX以预防出血。B型血友病的基因治疗旨在建立持续的因子IX活性，从而在无需繁重的因子IX替代治疗的情况下预防出血。
在这项开放标签的3期研究中，在进行因子IX预防的导入期（≥6个月）后，我们对54例B型血友病男性患者（因子IX活性≤正常值的2%）输注了一次表达帕多瓦因子IX变体的腺相关病毒5（AAV5）载体（etranacogene dezaparvovec；每千克体重2×10基因组拷贝），无论其是否预先存在AAV5中和抗体。主要终点是年化出血率，在一项非劣效性分析中进行评估，该分析比较了etranacogene dezaparvovec治疗后第7至18个月的年化出血率与导入期的年化出血率。etranacogene dezaparvovec的非劣效性定义为年化出血率比值的双侧95% Wald置信区间的上限小于非劣效界值1.8。还评估了优越性、其他疗效指标和安全性。
年化出血率从导入期的4.19（95%置信区间[CI]，3.22至5.45）降至治疗后第7至18个月的1.51（95% CI，0.81至2.82），率比为0.36（95% Wald CI，0.20至0.64；P<0.001），表明与因子IX预防相比，etranacogene dezaparvovec具有非劣效性和优越性。治疗后6个月时，因子IX活性较基线水平平均增加了36.2个百分点（95% CI，31.4至41.0），18个月时增加了34.3个百分点（95% CI，29.5至39.1），治疗后时期每位参与者每年因子IX浓缩物的使用量平均减少了248,825 IU（所有三项比较的P<0.001）。在给药前AAV5中和抗体滴度低于700的参与者中观察到了疗效和安全性。未发生与治疗相关的严重不良事件。
就年化出血率而言，etranacogene dezaparvovec基因治疗优于预防性因子IX，且安全性良好。（由uniQure和CSL Behring资助；HOPE - B临床试验注册号，NCT03569891。）
